title: High-dose enzyme replacement therapy in murine Hurler syndrome.
abstract: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from deficiency of α-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood-brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6 mg/kg, once per week, 4 weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, USA; Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ou
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Herzog
authors.affiliation: Research Animal Resources, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Koniar
authors.affiliation: Research Animal Resources, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Gunther
authors.affiliation: Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA. Electronic address: whitley@umn.edu.
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D056947:Enzyme Replacement Therapy; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000097:blood / Q000172:deficiency* / Q000493:pharmacokinetics* / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D007068:Iduronidase
keywords: BBB; Blood–brain-barrier; ERT; Enzyme replacement therapy; High dose; Hurler syndrome; IDUA; MPS; Mucopolysaccharidosis I; blood–brain-barrier; enzyme replacement therapy; mucopolysaccharidosis; α-l-iduronidase